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Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage.

Ren M, Tidwell JA, Sharma S, Cowell JK - PLoS ONE (2012)

Bottom Line: Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia.The B220(-) phenotype was retained in one of the cell lines while the other was B220(+).When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks.

View Article: PubMed Central - PubMed

Affiliation: Georgia Health Sciences University Cancer Center, Georgia Health Sciences University School of Medicine, Augusta, Georgia, United States of America.

ABSTRACT
Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+) IgM(-) CD43(+) immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+) IgM(-) CD43(+) were also either B220(+) or B220(-), suggesting a block in differentiation at the pro-B cell stage. The B220(-) phenotype was retained in one of the cell lines while the other was B220(+). When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

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Related in: MedlinePlus

Karyotypic analysis of B-lymphoma cell lines.CGH analysis (A) of BBC1 (above) and BBC2 (below) show distinct chromosome changes in the two cell lines. SKY analysis of BBC1 cells (B) demonstrates extensive aneuploidy and, in one metaphase, a t(4;14) non-reciprocal chromosome translocation.
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pone-0038265-g005: Karyotypic analysis of B-lymphoma cell lines.CGH analysis (A) of BBC1 (above) and BBC2 (below) show distinct chromosome changes in the two cell lines. SKY analysis of BBC1 cells (B) demonstrates extensive aneuploidy and, in one metaphase, a t(4;14) non-reciprocal chromosome translocation.

Mentions: Analysis of the chromosomes from the BBC1 cell line at an early stage (passage 5–10) using Spectral Karyotyping (SKY), demonstrated highly unstable karyotypes with multiple trisomies and a large variation in the chromosome composition between individual cells. Examples in Figure 5 show different clones within the parent cell population. The only chromosome translocation identified was a t(4;14) which was only seen in 3/51 metaphases analyzed and to our knowledge has not been reported previously. Comparative genome hybridization (CGH) analysis at a later passage (>50) demonstrated even further evolution of the chromosome content (Figure 5) with many whole chromosome losses and gains. CGH analysis of BBC2 similarly showed extensive chromosome aneuploidy where some of the changes were in common with BBC1 cells, although others were specific to BBC2. Common changes in the two cells lines were; −1, −2, +3, +5, +6, +8, −9, +10, +15 and −16. The high level of aneuploidy in these B-lymphoma cell lines is in contrast with those seen in the T-lymphoma cell line carrying the ZNF198-FGFR1 chimeric kinase [15] where only minimal aneuploidy was noted with a deletion of the TCRA locus on chromosome 14. This deletion was not seen in the BBC1/2 cell lines.


Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage.

Ren M, Tidwell JA, Sharma S, Cowell JK - PLoS ONE (2012)

Karyotypic analysis of B-lymphoma cell lines.CGH analysis (A) of BBC1 (above) and BBC2 (below) show distinct chromosome changes in the two cell lines. SKY analysis of BBC1 cells (B) demonstrates extensive aneuploidy and, in one metaphase, a t(4;14) non-reciprocal chromosome translocation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368885&req=5

pone-0038265-g005: Karyotypic analysis of B-lymphoma cell lines.CGH analysis (A) of BBC1 (above) and BBC2 (below) show distinct chromosome changes in the two cell lines. SKY analysis of BBC1 cells (B) demonstrates extensive aneuploidy and, in one metaphase, a t(4;14) non-reciprocal chromosome translocation.
Mentions: Analysis of the chromosomes from the BBC1 cell line at an early stage (passage 5–10) using Spectral Karyotyping (SKY), demonstrated highly unstable karyotypes with multiple trisomies and a large variation in the chromosome composition between individual cells. Examples in Figure 5 show different clones within the parent cell population. The only chromosome translocation identified was a t(4;14) which was only seen in 3/51 metaphases analyzed and to our knowledge has not been reported previously. Comparative genome hybridization (CGH) analysis at a later passage (>50) demonstrated even further evolution of the chromosome content (Figure 5) with many whole chromosome losses and gains. CGH analysis of BBC2 similarly showed extensive chromosome aneuploidy where some of the changes were in common with BBC1 cells, although others were specific to BBC2. Common changes in the two cells lines were; −1, −2, +3, +5, +6, +8, −9, +10, +15 and −16. The high level of aneuploidy in these B-lymphoma cell lines is in contrast with those seen in the T-lymphoma cell line carrying the ZNF198-FGFR1 chimeric kinase [15] where only minimal aneuploidy was noted with a deletion of the TCRA locus on chromosome 14. This deletion was not seen in the BBC1/2 cell lines.

Bottom Line: Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia.The B220(-) phenotype was retained in one of the cell lines while the other was B220(+).When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks.

View Article: PubMed Central - PubMed

Affiliation: Georgia Health Sciences University Cancer Center, Georgia Health Sciences University School of Medicine, Augusta, Georgia, United States of America.

ABSTRACT
Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+) IgM(-) CD43(+) immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+) IgM(-) CD43(+) were also either B220(+) or B220(-), suggesting a block in differentiation at the pro-B cell stage. The B220(-) phenotype was retained in one of the cell lines while the other was B220(+). When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

Show MeSH
Related in: MedlinePlus